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The dipeptidyl peptidase-IV inhibitor inhibits the expression of vascular adhesion molecules and inflammatory cytokines in HUVECs via Akt- and AMPK-dependent mechanisms

Hwang, Hwan-Jin, Chung, Hye Soo, Jung, Tae Woo, Ryu, Ja Young, Hong, Ho Cheol, Seo, Ji A., Kim, Sin Gon, Kim, Nan Hee, Choi, Kyung Mook, Choi, Dong Seop, Baik, Sei Hyun, Yoo, Hye Jin
Molecular and Cellular Endocrinology 2015 v.405 pp. 25-34
AMP-activated protein kinase, Western blotting, adhesion, anti-inflammatory activity, atherosclerosis, chemokine CCL2, dipeptidyl-peptidase IV, dose response, endothelium, enzyme inhibitors, foam cells, glycemic effect, human umbilical vein endothelial cells, interleukin-1beta, interleukin-6, lipopolysaccharides, low density lipoprotein, mitogen-activated protein kinase, phosphorylation, protective effect, transcription factor NF-kappa B, tumor necrosis factor-alpha
Recently, dipeptidyl peptidase-IV (DPP-IV) inhibitor, a major anti-hyperglycemic agent, has received substantial attention as a possible therapeutic target for inflammatory diseases such as atherosclerosis. However, the direct molecular mechanisms through which DPP-IV inhibitor mediates anti-inflammatory effects in vascular endothelial cells have not been clarified. The effects of the DPP-IV inhibitor, gemigliptin, were analyzed in human umbilical vein endothelial cells (HUVECs) and THP-1 cells. Using Western blotting, we demonstrated that gemigliptin efficiently increased the level of AMP-activated protein kinase (AMPK) and Akt phosphorylation in a dose-dependent manner. The levels of lipopolysaccharide (LPS)-mediated phosphorylated nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) were significantly decreased after gemigliptin treatment. Furthermore, gemigliptin reduced LPS-induced expression of adhesion molecules and inflammatory cytokines such as vascular cell adhesion molecule-1 (VCAM-1), E-selectin, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-1β (IL-1β), and IL-6 in HUVECs. In macrophage-like THP-1 cells, gemigliptin effectively inhibited LPS- and low-density lipoprotein (LDL)-induced foam cell formation. However, these anti-inflammatory and anti-atherosclerotic effects of gemigliptin in HUVECs and THP-1 cells were significantly reduced after treatment with an AMPK or an Akt inhibitor. Our results suggest that gemigliptin efficiently inhibited LPS-induced pro-inflammatory effects in vascular endothelial cells by attenuating NF-κB and JNK signaling via Akt/AMPK-dependent mechanisms. Therefore, the DPP-IV inhibitor, gemigliptin, may directly protect the vascular endothelium against inflammatory diseases such as atherosclerosis.